Until recently, theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed that the cause of migraine headache was vasodilatation of extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT1 agonist which does not cross the blood-brain barrier, induce contraction of cephalic vascular smooth muscle and are effective in the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work by Moskowitz has shown, however, that the occurrence of migraine headaches is independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia that innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT1D subtype, located on the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993. Sumatriptan, in fact, has high affinity for the 5-HT1B and 5-HT1D receptors, Ki=10.3 nM and 5.1 nM, respectively, which activity may be indicative of vasoconstrictive activity. Sumatriptan and similar compounds previously advanced for the treatment of migraine had tended to be selected on the basis of this vasoconstrictive activity under the premises of the prior art models for migraine.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT1. A human gene which expresses one of these 5-HT1 receptor subtypes, named 5-HT1F, was isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. It was found that sumatriptan, in addition to the above mentioned strong affinities for the 5-HT1B and 5-HT1D receptors, also has affinity for this receptor subtype, with a Ki of about 23 nM. This suggests a possible role of the 5-HT1F receptor in migraine.
Various 5-HT1F receptor agonists have subsequently been developed which have shown relative selectivity for the 5-HT1F receptor subclass and it has been shown that such selectivity generally reduces the vasoconstrictive activity characteristic of other compounds advanced as potential agents for the treatment of migraine and associated disorders.
Included among these 5-HT1F receptor agonists are compounds disclosed in the following:
U.S. Pat. Nos. 5,708,187 and 5,814,653, describing a family of 6-substituted-3-amino(alkyl)-tetrahydrocarbazoles and 7-substituted-4-amino(alkyl)cyclohepta[7,6b]Indoles;
U.S. Pat. Nos. 5,521,196, 5,721,252, 5,521,197, and WO 96/29075, describing various families of 5-substituted piperidin-3-yl-indoles and 5-substituted 1,2,3,6 tetrahydropyridin-3-yl-indoles;
WO 97/13512 describing a family of 5-substituted 3-aminoethylindoles;
WO 98/46570 describing a family of 5-substituted indoles, pyrrolo[3,2-b]pyridines, benzofurans, and benzothiophenes, having the 3-position substituted with octahydroindolizinyl, octahydro-2H-quinolizinyl, decahydropyrido[1,2-a]azepinyl, 1,2,3,5,8,8a-hexahydroindolizinyl, 1,3,4,6,9,9a-hexahydro-2H-quinolizinyl, or 1,4,6,7,8,9,10,10a-octahydropyrido[1,2-a]azepinyl;
WO 98/20875 and WO 99/25348 describing two families of 5-substituted piperidin-3-yl-azaindoles and 5-substituted 1,2,3,6-tetrahydropyridin-3-yl-azaindoles;
WO 00/00487 describing a family of 5-substituted (piperidin-3-yl or 1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans, and benzothiophenes;
WO 98/08502 describing a family of 8-substituted-1,2,3,4-tetrahydro-2-dibenzofuranamines and 9-substituted-2-aminocyclohepta[b]benzofurans;
WO 98/55115 describing a family of 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and 4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides;
WO 98/15545 describing a select family of 3,5-disubstituted indoles and benzofurans;
WO 00/00490 describing a family of 5-allyl-substituted (piperidin-3-yl or 1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans, and benzothiophenes;
WO 00/47559 describing a family of 4-(3-substituted-benzoyl)piperidines;
WO 00/50426 describing a family of 3,5-disubstituted azabenzofurans; and
WO 00/34266 describing a family of 3-heteroaryl-5-[2-(aryl or heteroaryl)-2-oxoethyl]indoles.
There is an ongoing need for an improved method and process of synthesis for the pyridinoylpiperidine compounds described herein, where the yield is improved and the purity of the resulting compounds is improved, and larger scale synthesis is possible in support of development and ultimately commercialization. This application describes such improved methods of synthesis.